Limits...
Yersinia pestis endowed with increased cytotoxicity is avirulent in a bubonic plague model and induces rapid protection against pneumonic plague.

Zauberman A, Tidhar A, Levy Y, Bar-Haim E, Halperin G, Flashner Y, Cohen S, Shafferman A, Mamroud E - PLoS ONE (2009)

Bottom Line: Following subcutaneous infection, this strain had reduced ability to colonize internal organs, was unable to induce septicemia and exhibited at least a 10(7)-fold reduction in virulence.Yet, upon intravenous or intranasal infection, it was still as virulent as the wild-type strain.These observations have novel implications for the development of vaccines/therapies against Y. pestis and shed new light on the virulence strategies of Y. pestis in nature.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.

ABSTRACT
An important virulence strategy evolved by bacterial pathogens to overcome host defenses is the modulation of host cell death. Previous observations have indicated that Yersinia pestis, the causative agent of plague disease, exhibits restricted capacity to induce cell death in macrophages due to ineffective translocation of the type III secretion effector YopJ, as opposed to the readily translocated YopP, the YopJ homologue of the enteropathogen Yersinia enterocolitica Oratio8. This led us to suggest that reduced cytotoxic potency may allow pathogen propagation within a shielded niche, leading to increased virulence. To test the relationship between cytotoxic potential and virulence, we replaced Y. pestis YopJ with YopP. The YopP-expressing Y. pestis strain exhibited high cytotoxic activity against macrophages in vitro. Following subcutaneous infection, this strain had reduced ability to colonize internal organs, was unable to induce septicemia and exhibited at least a 10(7)-fold reduction in virulence. Yet, upon intravenous or intranasal infection, it was still as virulent as the wild-type strain. The subcutaneous administration of the cytotoxic Y. pestis strain appears to activate a rapid and potent systemic, CTL-independent, immunoprotective response, allowing the organism to overcome simultaneous coinfection with 10,000 LD(50) of virulent Y. pestis. Moreover, three days after subcutaneous administration of this strain, animals were also protected against septicemic or primary pneumonic plague. Our findings indicate that an inverse relationship exists between the cytotoxic potential of Y. pestis and its virulence following subcutaneous infection. This appears to be associated with the ability of the engineered cytotoxic Y. pestis strain to induce very rapid, effective and long-lasting protection against bubonic and pneumonic plague. These observations have novel implications for the development of vaccines/therapies against Y. pestis and shed new light on the virulence strategies of Y. pestis in nature.

Show MeSH

Related in: MedlinePlus

Kim53ΔJ+P is highly virulent following systemic or airway infection.(A) Systemic infection (i.v. inoculation). Groups of 6 mice were infected intravenously with a dose of 2×103 cfu of Kim53pGFP (circle) or Kim53ΔJ+P (triangle), and mortality was monitored daily for 14 days. (B) Airway infection (i.n. inoculation). Groups of 5 mice were infected intranasally with 6×104 cfu of Kim53pGFP (circle) or Kim53ΔJ+P (triangle). (C) Dissemination of Y. pestis strains to blood and internal organs following intranasal infection. Groups of 5 mice were infected intranasally with 2×105 cfu of Kim53pGFP (black symbol) or Kim53ΔJ+P (white symbol) and sacrificed 48 hours post-infection. Bacterial concentration in blood and total bacterial loads in lungs, mediastinal lymph nodes (MSLNs) and the spleen were determined as described in the legend to Figure 2.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2691952&req=5

pone-0005938-g003: Kim53ΔJ+P is highly virulent following systemic or airway infection.(A) Systemic infection (i.v. inoculation). Groups of 6 mice were infected intravenously with a dose of 2×103 cfu of Kim53pGFP (circle) or Kim53ΔJ+P (triangle), and mortality was monitored daily for 14 days. (B) Airway infection (i.n. inoculation). Groups of 5 mice were infected intranasally with 6×104 cfu of Kim53pGFP (circle) or Kim53ΔJ+P (triangle). (C) Dissemination of Y. pestis strains to blood and internal organs following intranasal infection. Groups of 5 mice were infected intranasally with 2×105 cfu of Kim53pGFP (black symbol) or Kim53ΔJ+P (white symbol) and sacrificed 48 hours post-infection. Bacterial concentration in blood and total bacterial loads in lungs, mediastinal lymph nodes (MSLNs) and the spleen were determined as described in the legend to Figure 2.

Mentions: In an attempt to gain deeper insight into the mechanisms involved in the observed attenuation of virulence of the Kim53ΔJ+P strain, mice were infected with 2,000 cfu intravenously (i.v.), thereby bypassing the subcutaneous barrier. Under these conditions, both Y. pestis strains, the YopP-expressing strain and the Kim53pGFP strain, caused 100% mortality with comparable mean time to death (MTTD) of 3.2 and 3.4 days, respectively (Figure 3A).


Yersinia pestis endowed with increased cytotoxicity is avirulent in a bubonic plague model and induces rapid protection against pneumonic plague.

Zauberman A, Tidhar A, Levy Y, Bar-Haim E, Halperin G, Flashner Y, Cohen S, Shafferman A, Mamroud E - PLoS ONE (2009)

Kim53ΔJ+P is highly virulent following systemic or airway infection.(A) Systemic infection (i.v. inoculation). Groups of 6 mice were infected intravenously with a dose of 2×103 cfu of Kim53pGFP (circle) or Kim53ΔJ+P (triangle), and mortality was monitored daily for 14 days. (B) Airway infection (i.n. inoculation). Groups of 5 mice were infected intranasally with 6×104 cfu of Kim53pGFP (circle) or Kim53ΔJ+P (triangle). (C) Dissemination of Y. pestis strains to blood and internal organs following intranasal infection. Groups of 5 mice were infected intranasally with 2×105 cfu of Kim53pGFP (black symbol) or Kim53ΔJ+P (white symbol) and sacrificed 48 hours post-infection. Bacterial concentration in blood and total bacterial loads in lungs, mediastinal lymph nodes (MSLNs) and the spleen were determined as described in the legend to Figure 2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2691952&req=5

pone-0005938-g003: Kim53ΔJ+P is highly virulent following systemic or airway infection.(A) Systemic infection (i.v. inoculation). Groups of 6 mice were infected intravenously with a dose of 2×103 cfu of Kim53pGFP (circle) or Kim53ΔJ+P (triangle), and mortality was monitored daily for 14 days. (B) Airway infection (i.n. inoculation). Groups of 5 mice were infected intranasally with 6×104 cfu of Kim53pGFP (circle) or Kim53ΔJ+P (triangle). (C) Dissemination of Y. pestis strains to blood and internal organs following intranasal infection. Groups of 5 mice were infected intranasally with 2×105 cfu of Kim53pGFP (black symbol) or Kim53ΔJ+P (white symbol) and sacrificed 48 hours post-infection. Bacterial concentration in blood and total bacterial loads in lungs, mediastinal lymph nodes (MSLNs) and the spleen were determined as described in the legend to Figure 2.
Mentions: In an attempt to gain deeper insight into the mechanisms involved in the observed attenuation of virulence of the Kim53ΔJ+P strain, mice were infected with 2,000 cfu intravenously (i.v.), thereby bypassing the subcutaneous barrier. Under these conditions, both Y. pestis strains, the YopP-expressing strain and the Kim53pGFP strain, caused 100% mortality with comparable mean time to death (MTTD) of 3.2 and 3.4 days, respectively (Figure 3A).

Bottom Line: Following subcutaneous infection, this strain had reduced ability to colonize internal organs, was unable to induce septicemia and exhibited at least a 10(7)-fold reduction in virulence.Yet, upon intravenous or intranasal infection, it was still as virulent as the wild-type strain.These observations have novel implications for the development of vaccines/therapies against Y. pestis and shed new light on the virulence strategies of Y. pestis in nature.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.

ABSTRACT
An important virulence strategy evolved by bacterial pathogens to overcome host defenses is the modulation of host cell death. Previous observations have indicated that Yersinia pestis, the causative agent of plague disease, exhibits restricted capacity to induce cell death in macrophages due to ineffective translocation of the type III secretion effector YopJ, as opposed to the readily translocated YopP, the YopJ homologue of the enteropathogen Yersinia enterocolitica Oratio8. This led us to suggest that reduced cytotoxic potency may allow pathogen propagation within a shielded niche, leading to increased virulence. To test the relationship between cytotoxic potential and virulence, we replaced Y. pestis YopJ with YopP. The YopP-expressing Y. pestis strain exhibited high cytotoxic activity against macrophages in vitro. Following subcutaneous infection, this strain had reduced ability to colonize internal organs, was unable to induce septicemia and exhibited at least a 10(7)-fold reduction in virulence. Yet, upon intravenous or intranasal infection, it was still as virulent as the wild-type strain. The subcutaneous administration of the cytotoxic Y. pestis strain appears to activate a rapid and potent systemic, CTL-independent, immunoprotective response, allowing the organism to overcome simultaneous coinfection with 10,000 LD(50) of virulent Y. pestis. Moreover, three days after subcutaneous administration of this strain, animals were also protected against septicemic or primary pneumonic plague. Our findings indicate that an inverse relationship exists between the cytotoxic potential of Y. pestis and its virulence following subcutaneous infection. This appears to be associated with the ability of the engineered cytotoxic Y. pestis strain to induce very rapid, effective and long-lasting protection against bubonic and pneumonic plague. These observations have novel implications for the development of vaccines/therapies against Y. pestis and shed new light on the virulence strategies of Y. pestis in nature.

Show MeSH
Related in: MedlinePlus